This proposal represents a continuation of research in this laboratory which had previously demonstrated that experimental PKU produces an age-dependent, brain specific disaggregation of polyribosomes which, in turn produce an inhibitor of in vitro protein synthesis. The polysome disaggregation was attributed to the severely depleted brain tryptophan levels. In the 02 year of this grant we propose to investigate the consequences of increased cyclic AMP protein phosphorylation we have found in experimental PKU, and the possibility that in PKU increased phosphorylation of myelin basic protein leads to a failure of this protein to be inserted into myelin. Such a finding would explain the demyelination which others have reported to characterize PKU. We further plan to examine nucleotide pools in brain in animal models of PKU and to determine if reduced levels of ATP result in a failure to adenylate mRNA, making polysomes poly A-poor, and thus more labile to endogenous RNase. In the third stage of our proposed research, phenylethylamine levels in brain will be measured during hyperphenylalaninemia in order to determine the contribution of this compound to the neurologic dysfunction and pathology of PKU. We plan to determine biogenic amine levels in physiological fluids from a patient with PKU due to pteridine reductase deficiency to learn if the neurological signs he displays are related increases in phenyethylamine or decreases in amine neurotransmitters. Similar studies will be done on other patients who display familial cerebral palsy to determine if common metabolic determinants link CP and PKU due to pteridine reductase deficiency. BIBLIOGRAPHIC REFERENCES: Tolerance of Protein and Linked Synthesis to Mild Hyperphenylalaninemia in Developing Rat Brain, R.L. Geison and F.L. Siegel (1975) Brain Res. 92, 431-441. Isolation and Purfication of a Calcium-Binding Protein from Electroplax of Electrophorus Electricus, S.R. Childers and F.L. Siegel (1975) Biochem. Biophys. Acta 405, 99-108.